The research program funded by R01 013806 is focused on liver fibrosis progression in HIV/HCV coinfected persons. Liver disease is one of the leading causes of death in HIV infected persons, and its public health importance is expected to increase. As treatments for both HIV and HCV improve, the important clinical questions now are treatment-related. Does antiretroviral therapy (ART) affect progression of liver disease and therefore need to be given to HIV/HCV coinfected persons even at high CD4+ lymphocyte counts? Is suppression of HCV replication by treatment sufficient to stop fibrosis progression? Does the chronic immune activation caused by HIV contribute to IFN resistance and can ART diminish that effect? In the next funding cycle, we plan to answer these and other questions related to the "treated" history of HIV/HCV coinfected persons by a series of integrated clinical and laboratory studies that build on the models of natural history and pathogenesis that we and others have developed over the past decade. The specific aims are as follows: Aim 1 is to test the hypothesis that effective antiretroviral therapy reduces progression of liver fibrosis in HIV/HCV coinfected persons. Aim 2 is to test the hypothesis that suppression of HCV replication by treatment reduces liver fibrosis progression in HIV/HCV coinfected persons. Aim 3 is to test the hypothesis that interferon alfa (IFN) sensitivity is improved by antiretroviral therapy. The aims of prior funding cycles have been accomplished and reported among 25 peer reviewed articles supported by R01 013806. The current aims are revised to answer significant scientific questions during the next period using innovative research tools. There is a high likelihood that these studies will inform U.S. Public Health Service guidelines on when to start antiretroviral therapy and provide a scientific basis for existing guidelines governing treatment of HCV infection in persons with HIV. PUBLIC HEALTH RELEVANCE: The proposed research is designed to guide significant clinical decisions, such as when to start antiretroviral therapy in the 25% of HIV infected persons who have chronic hepatitis C and whether treatment for HCV infection can be justified to prevent progression of liver disease. The studies might also explain why treatments for chronic hepatitis C are not as effective in persons dually infected with HIV.